Prior Authorization Review Panel MCO Policy Submission

Prior Authorization Review Panel MCO Policy Submission

A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review.

Plan: AmeriHealth Caritas Pennsylvania Community HealthChoices

Policy Number: CCP.1079

Policy Name: Serum biomarkers for liver fibrosis

Submission Date: January 31, 2020

Effective Date: June 1, 2014 Revision Date: January 7, 2020

Type of Submission ? Check all that apply:

New Policy Revised Policy* Annual Review ? No Revisions Statewide PDL

*All revisions to the policy must be highlighted using track changes throughout the document.

Please provide any clarifying information for the policy below: Please see revisions below using tracked changes.

Name of Authorized Individual (Please type or print): William D. Burnham, MD

Signature of Authorized Individual:

CCP.1079

Serum biomarkers for liver fibrosis

Clinical Policy ID: CCP.1079

Recent review date: 1/2020

Next review date: 5/2021

Policy contains: FIBROSpect? II (PROMETHEUS Laboratories, San Diego, California); FibroSURE? (LABCORP?, Burlington, North Carolina); Chronic hepatitis C virus infection.

AmeriHealth Caritas Pennsylvania Community HealthChoices has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas Pennsylvania Community HealthChoices' clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of "medically necessary," and the specific facts of the particular situation are considered by AmeriHealth Caritas Pennsylvania Community HealthChoices when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas Pennsylvania Community HealthChoices' clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas Pennsylvania Community HealthChoices' clinical policies are reflective of evidencebased medicine at the time of review. As medical science evolves, AmeriHealth Caritas Pennsylvania Community HealthChoices will update its clinical policies as necessary. AmeriHealth Caritas Pennsylvania Community HealthChoices' clinical policies are not guarantees of payment.

Coverage policy

HCV FibroSURE is clinically proven and, therefore, medically necessary for the pre-treatment identification of clinically significant, advanced liver fibrosis (e.g., Metavir stages 3) in members with chronic hepatitis C virus infection when both criteria are met (American Association for the Study of Liver Diseases and Infectious Diseases Society of America, 2018; LabCorp, 2019; Houot, 2016):

? The test results will impact treatment decisions. ? The test is performed only in Clinical Laboratory Improvement Amendments-certified, validated reference

laboratories. The following tests are investigational and, therefore, not medically necessary:

? NASH FibroSURE. ? ASH FibroSURE. ? FIBROSpect II.

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Limitations

All other uses of FIBROSpect II or FibroSURE are not medically necessary, including population screening, disease monitoring, or treatment monitoring.

HCV FibroSURE is not medically necessary:

? When used in combination with other serum liver fibrosis biomarkers (e.g., fibrosis-4 index or the aspartate aminotransferase-platelet ratio index) (Koksal, 2018; Thiele, 2018; Voican, 2017).

? In members with conditions that may affect test accuracy, for example(Nguyen, 2011): - Acute hemolysis. - Gilbert's disease. - Extrahepatic cholestasis. - Post transplantation state. - Renal insufficiency. - Increased 2-macroglobulin and haptoglobin from systemic or hepatic inflammation.

? In members with no or cured hepatitis C virus infection. ? In members with clinically evident cirrhosis.

Alternative covered services

? Alanine transaminase test. ? Aspartate aminotransferase test. ? Computed tomography. ? Magnetic resonance imaging. ? Fibrogen test. ? Haptoglobin test. ? Liver biopsy. ? Total bilirubin test. ? Transient elastography (Fibroscan?; Echosens Co., Paris, France). ? Ultrasound.

Background

In the United States, an estimated 150,000 persons are diagnosed annually with chronic liver disease, and nearly 30,000 have cirrhosis at initial presentation (Thein, 2008). The development and progression of hepatic fibrosis can mediate disease-related complications of cirrhosis. The progression of hepatic fibrosis is a nonlinear, discontinuous process that is greatly influenced by factors such as age, sex, race, alcohol exposure, and obesity. Obtaining further information about the degree of liver injury from hepatitis C is an important factor in deciding to pursue or defer antiviral therapy (Thein, 2008).

An accurate assessment of hepatic fibrosis is an important prognostic indicator of hepatitis C virus disease progression and clinical outcomes. Individuals with severe fibrosis require surveillance monitoring for liver cancer, esophageal varices, and hepatic function, and may require a longer duration of anti-viral treatment.

The clinical standard for diagnosis and therapy planning is histopathological examination of a percutaneous liver biopsy, but it is an invasive procedure that often requires multiple passes, has a small but significant risk for procedure-related complications, and is subject to inter- and intra-observer variability in biopsy interpretation (Nguyen, 2011). Inaccurate staging from sampling error is estimated to occur in up to 25 percent of cases, and substantial discordance in fibrosis stage involving the right and left liver lobes in the same patient may cause sampling variability. Finally, patients may be reluctant to undergo invasive testing (Nguyen, 2011).

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A variety of serum markers have been developed to identify patients who are at risk for clinically significant hepatic fibrosis (defined by Metavir stages F2 to F4). These markers are classified as direct (representing components of extracellular matrix) or indirect (reflecting hepatic inflammation and function). Indirect markers may be used alone or combined with direct markers to form panels. The practical advantages of these blood tests include their noninvasiveness, potential for widespread availability, and reproducibility when serial examinations are performed using the same laboratory.

Two indirect serum biomarkers marketed in the United States are FibroSURE (known as Fibrotest in Europe) and FIBROSpect? II. FibroSURE consists of a six-biomarker panel (alpha-2-macroglobulin, haptoglobin, gamma-globulin, apolipoprotein A1, gamma-glutamyl transferase, and total bilirubin) that provides Metavir fibrosis staging and necroinflammatory grading to monitor liver status in patients with chronic liver disease (LabCorp, 2019). FibroSURE can be performed using a variety of components in assays and analyzers. To ensure reproducibility, FibroSURE can only be performed in Clinical Laboratory Improvement Amendmentscertified, validated reference laboratories (e.g., LabCorp) as opposed to local outpatient or hospital-based labs where other testing is typically performed (LabCorp, 2019; Nguyen, 2011).

Three FibroSURE tests are available, and the parameters of each FibroSURE testing panel are specific to the liver disease for which it was developed (LabCorp, 2019):

? HCV FibroSURE for: 1) assessment of liver status following a diagnosis of hepatitis C virus; 2) baseline determination of liver status before initiating anti-viral therapy; 3) posttreatment assessment of liver status six months after completion of therapy; and 4) noninvasive assessment of liver status in patients who are at increased risk of complications from a liver biopsy.

? NASH FibroSURE for noninvasive assessment of liver status in patients with nonalcoholic fatty liver disease.

? ASH FibroSURE for noninvasive assessment of liver status in patients with suspected alcoholic liver disease.

FIBROSpect uses a quantitative analysis of hyaluronic acid, tissue inhibitor of metalloproteinase and 2macroglobulin, which applies an algorithm to predict the likelihood of liver fibrosis in patients with hepatitis C with no indeterminate results (PROMETHEUS, 2017). PROMETHEUS Laboratories Inc. is Clinical Laboratory Improvement Amendments-certified and accredited by the College of American Pathologists. This test is only offered at PROMETHEUS Laboratories (PROMETHEUS, 2017).

Findings

We identified six systematic reviews for this policy. No economic analyses were identified.

For the FIBROSpect test, two systematic reviews with overlapping literature found insufficient evidence to determine either its efficacy for detecting fibrosis or disease severity in hepatitis C virus-infected populations (Chou, 2013; Smith, 2009). FIBROSpect has a significant false-negative rate, indicating that it fails to detect cases of clinically significant fibrosis detected by biopsy. Studies generally enrolled populations with a high prevalence of clinically significant fibrosis, which may overestimate accuracy estimates, and used a variety of gold standards. Thus, its "true" discriminative ability has not been tested adequately. Finally, there is a lack of evidence of the effect of FIBROSpect testing on patient management or patient outcomes.

For FibroSURE, five systematic reviews with overlapping literature found insufficient evidence to determine either its efficacy for detecting fibrosis or disease severity or impact on patient outcomes in hepatitis C virus-infected populations (Cholongitas, 2010; Chou, 2013; Shaheen, 2007, 2008; Smith, 2009). Test scores at the extremes of the fibrosis measures (e.g., Fibrotest < 0.20 or > 0.60), which are seen in approximately 50 percent of patients, have acceptable predictive values (80 percent range), but test scores with intermediate values are not accurate

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enough to replace liver biopsy. False-positive results may be attributed to decreases in haptoglobin from hemolysis, increases in total bilirubin from conditions such as Gilbert's syndrome and cholestasis, and increases in 2-macroglobulin and haptoglobin from systemic or hepatic inflammation (Nguyen, 2011).

Overall, variability in methods and poor interobserver agreement for histological staging limit the diagnostic efficacy of noninvasive biomarkers such as FIBROSpect and FibroSURE. Noninvasive biomarkers produce continuous scores that are then correlated with categorical variables (i.e., the stage scores), which are only descriptive categories of fibrosis. There are differences among the various histological scoring systems, and they lack an arithmetical progression. Quantitative measurement of liver fibrosis would be a more appropriate comparator to these test scores, but the relationship between clinical correlations and quantitative measurement of liver fibrosis has not been extensively evaluated (Cholongitas, 2010).

The National Institutes of Health (2002) issued a consensus statement on the management of hepatitis C that considered the use of noninvasive tests for assessing liver fibrosis. It concluded noninvasive tests were not adequate substitutes for liver biopsy, as they were not widely available or well validated; no single test or panel of serologic markers can provide an accurate assessment of intermediate stages of hepatic fibrosis. Since then, several organizations have issued evidence-based recommendations and arrived at similar conclusions, despite wider availability of these tests (Centers for Disease Control and Prevention, 2013; Ghany, 2009; Mofenson, 2009; Moyer, 2013; Rockey, 2009).

In 2015, one systematic review update (Selph, 2014) of a previously included review (Chou, 2013), one costeffectiveness analysis (Crossan, 2015), and one guideline (American Association for the Study of Liver Diseases, 2014) were added to the policy. The new information does not change the previous findings or the clinical policy. Therefore, no changes to the policy are warranted.

In a previously included systematic review, Chou (2013) had omitted a significant number of published studies from summary estimates, because they provided insufficient information to calculate diagnostic accuracy. Selph (2014) obtained the unpublished data and recalculated diagnostic accuracy estimates. The additional data had no appreciable impact on diagnostic accuracy estimates for diagnostic tests for hepatic fibrosis.

Crossan (2015) assessed the diagnostic accuracy and cost-effectiveness of noninvasive liver tests in adults with chronic liver disease from the perspective of current practice in the United Kingdom. Fibrotest was the most widely assessed commercial test, and FIBROSpect was studied only in hepatitis C virus populations for the stages of interest in their models. Noninvasive liver tests were compared with each other, sequential testing strategies, biopsy, and strategies including no testing. The overall robustness of included studies was poor, and the economic benefits of noninvasive liver tests varied according to the cause of the liver disease.

For persons with an active hepatitis C virus infection, the best option is to treat all regardless of stage of liver disease. For persons with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus, this is also the case if the higher bound of the standard cost-effectiveness threshold is considered acceptable. These findings would apply in settings similar to the United Kingdom; however, in resource-poor settings, a treat-all strategy may not be possible. In this case, a noninvasive test may be a better diagnostic option than liver biopsy.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (2014), in collaboration with the International Antiviral Society?USA, recommend assessing the degree of hepatic fibrosis, using liver biopsy, imaging, and/or noninvasive markers to determine the urgency for treatment. Indirect serum markers, direct serum markers, and vibration-controlled transient elastography may be considered. However, no single method has sufficiently high accuracy, and each test must be interpreted carefully. Based on the results of Selph (2014), these tests are, at best, only moderately useful for identifying clinically significant fibrosis or cirrhosis. The most efficient approach to fibrosis assessment is to combine direct biomarkers and vibration-controlled transient elastography. A biopsy should be considered for any patient who has discordant results between the two modalities that would affect clinical decision making.

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